Abstract

Pulmonary involvement is a common complication of vasculitides, especially small vessel
vasculitides. This review provides an overview of vasculitic manifestations of the
lung as well as of other organs involved in vasculitides. Furthermore, it provides
the diagnostic procedures required to asses a patient with vasculitic lung involvement
and gives an overview of current treatment strategies.

Introduction

The vasculitides comprise a heterogenous group of conditions that are currently classified
according to the size of blood vessels predominantly involved [1,2]. Typically, vasculitides involving predominantly small- to medium-size vessels are
associated with multiple organ involvement, including a predilection for the lung,
whereas pulmonary involvement of large vessel vasculitides is rarer. This review therefore
focuses on small vessel vasculitides and their pulmonary manifestations: pulmonary
capillaritis leading to alveolar hemorrhage is the classic manifestation of small-vessel
vasculitis and occurs most frequently in the context of the anti-neutrophil cytoplasmic
antibody (ANCA)-associated vasculitides (AAVs). The AAVs represent the most frequent
underlying condition of alveolar hemorrhage. Wegener's granulomatosis (WG), microscopic
polyangiitis (MPA) and Churg-Strauss syndrome (CSS) share the features of small vessel
vasculitis and a (variable) association with ANCAs and are therefore termed AAVs.
Yet whereas MPA may be regarded as a 'pure' small- to medium-size vessel vasculitis,
the other two AAVs (WG and CSS) feature more than just vasculitic manifestations.
In WG the spectrum of organ manifestations encompasses inflammatory mass formation
('granulomatous disease'), which is most prevalent in the upper and lower respiratory
tracts and characterized by tumor-like infiltrative or destructive disease. In CSS,
'granuloma formation' may also be found, though less pronounced; furthermore, asthma,
hypereosinophilia and eosinophilic organ infiltration are hallmarks of CSS.

Wegener's granulomatosis

Clinical features and histology

From the clinical point of view, WG is characterized by two features: mass formation
and ANCA-associated small- to medium-size AAV. The former is usually restricted to
the upper and lower respiratory tracts and its characteristic histology features constitute
granulomatous and necrotizing inflammation, yet vasculitis may also be found within
the granulomatous inflammation [2]. The latter may affect virtually any organ, with a predilection for lung and kidney
involvement (necrotizing, predominantly small-vessel pauci-immune vasculitis, that
is, manifesting as pulmonary capillaritis and crescentic glomerulonephritis) [3,4]. There is some evidence from in vitro and in vivo studies that ANCAs play a crucial role in the mediation of small-vessel vasculitis
[5-7]. In WG, ANCAs are mainly directed against Proteinase 3 [4] and are implicated in the activation of polymorphonuclear neutrophils by interacting
with Proteinase 3 expressed on the plasma membrane of these [5].

Disease stages

According to a concept by Fienberg [8], WG starts as 'granulomatous' disease of the upper and lower respiratory tracts and
subsequently progresses to generalized ('systemic') disease characterized by clinical
vasculitis manifestations, such as pulmonary capillaritis or necrotizing glomerulonephritis.
This concept has been incorporated in the European definition of disease stages of
AAV introduced in 1995 [9] and has been updated several times since then. In the current definitions [10], the localized disease stage, defined as manifestations restricted to the respiratory
tract (that is, rhinitis, sinusitis, pulmonary masses) with no clinical signs of vasculitis
(no pulmonary capillaritis), is differentiated from the systemic disease stages (early
systemic, generalized and severe disease), all of which are associated with clinical
signs of vasculitis. In the systemic disease stages, patients usually present with
pronounced constitutional symptoms (weakness, fever, weight loss). Whereas early systemic
disease is considered non-life-threatening (that is, occurring with arthritis, episcleritis
or purpura), generalized disease is defined as organ- or life-threatening (that is,
due to glomerulonephritis or alveolar hemorrhage). In severe disease, organ failure
has occurred due to systemic vasculitis manifestations (that is, renal failure; Table
1). The definition of these disease and activity stages [10] has facilitated the generation of evidence-based, stage-adapted treatment regimens.
For most disease stages (except for localized disease), evidence from controlled trials
is available to guide treatment decisions [11].

Respiratory tract manifestations

WG usually starts with symptoms due to upper respiratory tract involvement: manifestations
affecting the nasal and oral cavity, the sinuses and the trachea are reported to occur
in 75 to 93% of patients at diagnosis and in up to 99% during the course of the disease
[3,4,12]. Upper respiratory tract involvement not only occurs early in the disease course,
but is the most frequent manifestation of WG [4], and for these two reasons is indicative of WG: patients typically present with rhinosinusitis
with bloody discharge, crusting and epistaxis. Nasal crusting ('golden crusts') is
a typical finding of endoscopic evaluation.

Granulomatous inflammation and/or mass formation may be found in the nasal cavity,
sinuses and within the orbits but also frequently in the lower respiratory tract as
pulmonary 'granuloma' [3,4] (Figure 1). Orbital masses, either perforating from the sinuses or developing within the orbit
in isolation, are a serious complication of upper respiratory tract disease in 15
to 20% of patients [4]. The nature of granulomatous inflammation is destructive, as a significant proportion
of patients develop signs of cartilage and bone erosion during the course of disease
(that is, saddle nose deformity or orbital wall destruction), as has recently been
shown in a study of localized WG patients [13]. Trachea and bronchi may also be affected by ulcerative or granulomatous inflammation,
which may result in subglottic or bronchial stenosis.

The overall incidence of pulmonary involvement is frequent (between 60% and 85%) and
constitutes 'granulomatous' as well as 'vasculitic' manifestations [3,4,12]. Pulmonary nodules/masses ('granuloma') have been described on conventional radiography
in around 60% of cases [3]. Diffuse alveolar hemorrhage due to vasculitis has been documented in 7 to 45% of
patients [3,4] (Figure 2).

Figure 2.Diffuse bilateral infiltrations on plain X-ray due to alveolar hemorrhage as occurring
in Wegener's granulomatosis, micorscopic polyangiitis and Churg-Strauss-syndrome. In order to verify that infiltrations are due to alveolar hemorrhage, bronchoalveolar
lavage is required.

Respiratory tract manifestations of the localized disease stage

The occurrence of 'granulomatous' manifestations of the upper and/or lower respiratory
tract with no clinical signs of vasculitis has been defined as the localized stage
(formerly the initial phase) [10], which is considered a transient stage before the patient develops systemic, clinical
manifestations of vasculitis (which is present in all other disease stages). Yet,
around 5 to 10% of patients remain in this disease stage and do not progress to systemic
disease [13]. As outlined above, rhinitis, sinusitis, granulomatous mass formation (in sinuses,
orbita and lung) as well as ulcerative or granulomatous and stenotic inflammation
of trachea and bronchi (subglottic and bronchus stenosis) are manifestations of the
localized stage. Cavitating nodules or masses with a diameter of greater than 3 cm
on high-resolution computed tomography (HRCT) as well as parenchymal opacification
are considered active lesions [14,15]. In contrast to generalized disease, the localized stage has been presumed mild and
non-organ threatening, a finding that has recently been refuted by a cohort study
on localized WG [13]. In this study, all patients developed upper respiratory tract involvement. Furthermore,
a significant proportion of patients developed destructive lesions within the upper
respiratory tract: 30% saddle nose deformity; 28% nasal septal perforation; 18% suffered
from space-consuming granulomatous masses leading to subglottic inflammation and stenosis;
20% had pulmonary involvement with pulmonary mass formation. Due to resistant tumor-like
mass formation and/or destructive, infiltrating inflammation, nearly 50% required
highly potent immunosuppression (with cyclophosphamide) and 66% of patients acquired
some kind of organ damage over the whole course of follow-up.

Respiratory tract manifestations of the generalized disease stage

'Granulomatous' manifestations may persist or even develop throughout the generalized
disease stage, yet this stage is, per definitionem, associated with organ- and or life-threatening vasculitis manifestations. In the
lung, diffuse alveolar hemorrhage (DAH) due to alveolar capillaritis is the classic
manifestation of this disease stage. DAH has been reported to occur in 7 to 45% of
patients and may develop in conjunction with glomerulo-nephritis, which is summarized
under the term pulmonary-renal syndrome. Hemoptysis and dyspnea are characteristic
clinical signs of DAH, although a significant proportion of patients with DAH presents
without hemoptysis. An increase in diffusing capacity of >30% is suggestive of DAH
in patients at risk. Diffuse uni- or bilateral alveolar shadowing on X-ray should
raise the suspicion of DAH. HRCT scans typically show diffuse ground glass opacities.
DAH can be confirmed by fiberoptic bronchoscopy, which may show diffuse bleeding arising
from the pulmonary parenchyma and/or increasingly bloody lavage fluid in consecutive
portions during bronchoalveolar lavage. The amount of alveolar hemorrhage may be semiquantitatively
assessed by the number and the intensity of staining of hemosiderinladen alveolar
macrophages ('Golden score'). DAH may manifest as subclinical disease, but bleeding
can also be severe and lead to a significant fall in hematocrit, hypovolemic shock
and respiratory insufficiency. Mortality of DAH in AAV depends on severity and is
estimated at 50 to 60% when mechanical ventilation is required [16,17].

Apart from DAH, pulmonary involvement may also be present in the form of alveolitis
that is not associated with capillaritis and DAH. Alveolitis is related to diffuse
or interstitial pulmonary infiltrates on X-ray and a ground-glass pattern in CT. Active
disease is associated with an increased neutrophil count in the broncho-alveolar lavage
fluid [18]. An elevation of CD4+ T lymphocytes may also be found, mainly in conjunction with an interstitial infiltrate
[18].

Microscopic polyangiitis

Clinical features, disease stages and histology

MPA may be regarded as 'pure' small- to medium-size vessel vasculitis that is associated
with a positive ANCA status in more than 90% of cases, usually with perinuclear ANCAs
(P-ANCAs) or myeloperoxidase-specific ANCAs (MPO-ANCAs). MPA has an incidence of three
people per million per year and shows a slight male predominance [19,20] with an average onset between 50 and 60 years of age. In contrast to WG, patients
with MPA do not present with a classic localized stage of the disease. Ear-nose-throat
(ENT) symptoms have been described to occur [20,21], but granulomatous tumor-like or destructive processes of the upper and lower respiratory
tract are lacking. At disease onset, constitutional symptoms are common [19,21]. Patients may present initially with either a non-life-threatening course ('early
systemic disease', that is, arthralgia, arthritis, episcleritis), which may progress
to 'generalized' disease, or acute organ- or life-threatening disease ('generalized'
or 'severe' disease stage, that is, necrotizing glomerulonephritis or DAH) within
days or weeks. Similar to WG, there is a predilection for vasculitic manifestations
of kidney (glomerulonephritis) and lung (alveolar capillaritis): glomerulonephritis
has been reported to occur in 80 to 100% of patients [19-22] and is even more frequent than in WG; and alveolar hemorrhage due to capillaritis
has been reported in 12 to 55% of patients [19-22] (Figure 2). In biopsy specimens, small- to medium-size necrotizing pauci-immune vasculitis
is to be found with no evidence of granuloma formation.

Respiratory tract manifestations

DAH is the classic pulmonary manifestation in MPA and has been described to occur
in 12 to 55% of patients [19-22]. MPA shows the highest frequency of DAH and/or glomerulonephritis among the AAVs,
occurring either as isolated organ involvement or together as pulmo-renal syndrome.
As in WG, it has a wide spectrum, ranging from asymptomatic disease to a severe life-threatening
stage.

Pulmonary fibrosis has been recognized as a pulmonary manifestation of MPA (Figure
3). Only few cases and a larger retrospective case series have been reported in the
literature, most of which demonstrated an association of pulmonary fibrosis with MPO-ANCA-positive
AAV or MPA [23-25], suggesting a pathogenic role of MPO or MPO antibodies in MPA-associated pulmonary
fibrosis. Pulmonary fibrosis may develop after other clinical manifestations of MPA,
but has also been reported to occur before disease onset [24], and it may have a usual interstitial pneumonia (UIP) or noninterstitial pneumonia
(NSIP) pattern on HRCT and is associated with lower total lung capacity and increased
mortality [26].

Churg-Strauss syndrome

Clinical features, disease stages and histology

CSS is characterized by peripheral blood hypereosinophilia, tissue eosinophilia, asthma
and vasculitis [1,2]. The association with ANCAs is less strong; ANCAs can be detected in around 40% of
individuals with CSS, in most cases P-ANCAs or MPO-ANCAs [27]. There is a substantial clinical overlap with the hypereosinophilic syndrome (HES).
In fact, in some cases it might be difficult to strictly differentiate between CSS
and HES. According to recent classification proposals, CSS may be seen as a subtype
of HES [28]. CSS usually develops in three distinct phases: the first phase is indistinguishable
from poorly controlled asthma and may last for several years; the second phase is
characterized by profound blood eosinophilia; and finally, with additional manifestations
of small vessel vasculitis or histological evidence of vasculitis, the diagnosis of
CSS can be established [29]. In general CSS may involve any organ system, although the lungs (90 to 100%), the
peripheral nervous system (approximately 70%), the skin (50 to 70%) and the heart
(approximately 50%) are predominantly affected [30,31]. According to the literature, ENT involvement is seen in about 50% of patients; in
our own experience, sinusitis, polyposis or rhinitis are found in more than 90% if
examination by an ENT specialist is part of the work-up (unpublished observation).
Constitutional symptoms are common.

ANCAs are correlated with distinct clinical manifestations: in ANCA-positive CSS,
classical vasculitis manifestations, such as glomerulonephritis, pulmonary vasculitis
with DAH or peripheral neuropathy, are more frequent, whereas heart-involvement is
seen more often in ANCA-negative CSS [29]. Evidence from genetic studies further supports the view of at least two distinct
disease subtypes [32].

In the absence of surrogate parameters for vasculitis, the evaluation of biopsy specimens
is crucial to differentiate between HES and CSS since the latter requires histological
evidence of necrotizing vasculitis as long as no clinical surrogate such as glomerulonephritis
is present. In the original publication by Churg and Strauss [33] three characteristic features were described: tissue eosinophilia, necrotizing vasculitis
and granuloma formation. Tissue infiltration by eosinophils is very common and believed
to represent a major pathogenic mechanism; however, it is not specific for CSS and
cannot aid delimitation towards HES.

Definitions for disease stages and activity should be used as suggested for AAV (Table
1), although the evidence for those definitions was derived mainly from studies in
WG and MPA. The Five Factor Score (FFS) for CSS was found to predict mortality and
should be used as a prognostic tool [34,35].

Respiratory tract manifestations

Respiratory tract involvement is very common in CSS. The vast majority of patients
(>90%) suffer from bronchial asthma. In spite of the high frequency of asthma in CSS
patients, clinical features of asthmatic manifestations and subtypes of asthma have
not yet been described in detail. There are no reliable markers to predict the development
of CSS in asthmatics. In the majority of patients asthma is characterized by adult
onset and a relatively low prevalence of inhalational allergies. Frequently, a tendency
to more severe or 'difficult to treat' asthma is observed. In more than 80% of cases
asthma precedes the onset of vasculitis by a median time of 4 years [36]. Lung function testing often shows persistent airflow obstruction in CSS patients
with asthma [37]. Some reports link the use of a leukotriene receptor antagonist to CSS, although
many experts believe that leukotriene receptor antagonists simply unmask CSS by allowing
for reduction of systemic steroids. In a recent study, however, the association between
leukotriene receptor antagonist and CSS could not be explained by steroid withdrawal
in the majority of cases [38].

Reported frequencies of nasal polyposis, sinusitis and rhinitis vary and, according
to our experience, are underestimated as long as no routine examination by an ENT
specialist and/or cranial MRI is included in the work-up procedure. Upper respiratory
tract manifestations in CSS can be distinguished from WG due to the lack of mass formation
and destruction. Granulomatous lesions are a feature in biopsy specimens, yet the
clinical or radio-logical appearance of granulomatous mass formation is usually not
seen in CSS.

Pleural effusions can be seen in 10% of cases and might either be a sign of congestive
heart failure due to heart involvement or a sequel of eosinophilic pleuritis.

Eosinophilic infiltration of the lung is common and may be detected as a patchy and
migratory infiltrate on plain X-ray (Figure 4). Bronchoalveolar lavage is performed in order to prove eosinophilic alveolitis,
and tissue infiltration may be seen in trans-bronchial lung biopsies. Other forms
of alveolitis and mixed patterns (neutrophilic and lymphocytic alveolitis) also occur
[39]. DAH as the clinical equivalent of lung capillaritis can occur but is less frequent
than in WG and MPA [30] (Figure 2).

Figure 4.Diffuse, shadowy infiltrate in a patient with Churg-Strauss syndrome (on the left),
promptly resolving under glucocortocoid therapy within 7 days (on the right).

Diagnostic procedure and therapy and outcome of AAV

Diagnostic work-up

AAV patients should undergo a standardized multidisciplinary evaluation in order to
determine disease stage and activity. It is recommended to treat AAV patients at or
in cooperation with specialist centers [11]. All AAV patients require a work-up that includes examination of lung (X-ray, lung
function testing and HRCT, and fiberoptic bronchoscopy with bronchoalveolar lavage
if necessary) and kidneys (ultrasound, assessment of creatinine clearance and microscopic
hematuria, red cell casts and proteinuria) and testing for ANCAs. In addition, WG
patients should be seen by an otorhinolaryngologist and CSS patients require assessment
of pulmonary function and allergy testing. At first presentation, confirmation of
diagnosis should be sought by biopsy - for example, nasal mucosa and lung or kidney
biopsy. Depending on disease symptoms and suspected organ manifestations, additional
evaluations by a neurologist, ophthalmologist and dermatologist and/or additional
technical examinations, such as MRI of sinuses and orbits, may be required.

Patients should be seen and evaluated in regular intervals (three- to six-monthly)
to assess disease activity and adapt immunosuppressive therapy. Ideally, patients
are evaluated by standardized and validated tools to assess disease activity and damage
(such as the Birming-ham Vasculitis Activity Score or the Vasculitis Damage Index)
[40,41].

Treatment and outcome of Wegener's granulomatosis and microscopic polyangiitis

Treatment follows a stage- and disease activity-adapted regimen due to evidence from
controlled trials [11]. For remission induction in WG and MPA, methorexate (MTX) should be used in non-organ-threatening
early systemic disease and cyclophosphamide in generalized disease in addition to
glucocorticoids [42,43]. Rituximab may be an alternative for cyclophosphamide in the future [44,45], even if not yet listed in the treatment recommendations as data have been published
only very recently. For severe disease, namely acute renal failure, additional plasma
exchange is recommended [46]. After successful remission induction (of 3 to 6 months), MPA and WG patients should
be switched to maintenance therapy with medium-potent immunosuppression (azathioprin,
MTX or leflunomide) [47-49]. It is recommended that the glucocorticoid dose should not exceed 10 mg prednisone/day
during maintenance. It is not yet known how long maintenance therapy is required but
this is being investigated in current trials.

Treatment of localized WG and refractory disease represent the current challenges
in the treatment of AAV. For localized disease, no controlled trials are available
to support therapy decisions. Trimethoprim/sulfomethoxazole may be used for remission
induction in upper airway disease in WG [50,51] although it was not sufficient to control disease activity in a significant proportion
of patients with persistent localized WG [13]. In clinical practice, patients in the localized disease stage are treated according
to disease activity and severity: manifestations such as granulomatous sinusitis or
subglottic stenosis may be treated with MTX. In the case of disease progression (that
is, granulomatous sinusitis perforating the orbital wall and affecting the optic nerve)
patients usually receive highly potent immunosuppression.

In spite of the use of highly potent and potentially toxic immunosuppression, such
as cyclophosphamide, around 15 to 20% of patients (localized and generalized) do not
respond to therapy ('refractory disease') [4,13]. In this situation, rituximab, infliximab, deoxyspergualin, antithymocyte globulin,
mycophenolate mofetil or intra-venous immunoglobulins are recommended [11], although controlled trials to support these recommendations are still lacking.

Older age, kidney involvement with impaired renal function, pulmonary manifestations
at diagnosis and absence of ENT symptoms have been related to an adverse outcome and
increased mortality [4,52,53]. Whereas several studies published in the 1990s showed an increased mortality of
WG and MPA compared to the general population [54-57], a decrease in the standardized mortality ratios was reported in Swedish patients
diagnosed before and after 1996 [58]; furthermore, a recent study reported no (more) increased mortality rates in WG patients
diagnosed in the 1990s [59]. The evidence from controlled trials and the implementation of stage-and disease
activity-adapted regimens have particularly contributed to the improved outcome. Regardless,
mortality rates during the first year after diagnoses remain excessively high (50%),
especially in those patients who are severely diseased (in the generalized or severe
disease stage) and treated with highly potent immunosuppression [60]. Interestingly, patients died rather from infections than from acute vasculitis [60].

Treatment and outcome of Churg-Strauss syndrome

In general, principles of treatment for CSS are the same as for the other AAVs. A
stage- and disease activity-adapted approach is recommended. To guide therapy, the
FFS as an additional instrument should be used [34]. Glucocorticoids (GCs) represent the mainstay of CSS treatment. In most cases relatively
high doses have to be used for longer periods of time. As evidence accumulates that
GCs are also the most significant risk factor for severe infections (see below) and
long-term use is associated with a high burden of co-morbidity, therapy should aim
to keep GC dose as low as possible. Concomitant treatment with high-dose inhaled corticosteroids
may help to control asthma in CSS and lower systemic GC doses, although prospective
data in this respect are not available. Medium-potent immunosuppressants, such as
MTX or azathioprine, may be used for steroid sparing. In non-life- or organ-threatening
CSS, for example, MTX might be used for induction of remission but subsequent relapse
rates are high [61]. A FFS of ≥1 usually triggers intense immunosuppression with cyclophosphamide [35]. Further indications for the use of cyclophosphamide are severe peripheral nerve
involvement or failure of medium-potent drugs to control disease activity. Most experts
recommend maintenance therapy after attaining remission for years, although proof
of this concept is lacking in CSS.

Despite treatment with GCs and cyclophosphamide, about 10% of patients show refractory
disease courses. The reported 5-year mortality rates in recent series are about 80%
[62]. Several salvage therapies have been reported in case reports or small case series.
Interferon-α is capable of inducing remission but long-term results are disappointing
[63,64]. Rituximab, as in WG and MPA, may be a promising approach but data from larger series
are still lacking [65]. Some efficiency was reported with tumor necrosis factor-α blocking agents [66].

A recently published case series reported the steroid sparing potential of mepolizumab,
an IL-5 antibody, but failure to induce remission [67]. In another trial the steroid sparing potential was confirmed and the capability
of mepolizumab to induce remission in refractory and relapsing CSS was shown [68]. Targeting IL-5 therefore represents the first targeted approach in CSS and warrants
further investigations.

Pulmonary manifestations of other vasculitides

Among the small vessel vasculitides, Goodpasture's syndrome (GPS) is responsible for
around 20% of alveolar hemorrhage due to pulmonary capillaritis. GPS is associated
with antiglomerular basement membrane antibodies (ABMAs), and is rarely confined to
the lungs but occurs usually in conjunction with glonerulonephritis (pulmonary-renal
syndrome). ABMAs target type IV collagen in basement membranes of lungs and kidneys,
which may become exposed and thereby accessible for ABMAs in the presence of inhalative
noxae such as cigarette smoke or respiratory infections. GPS typically affects young
adults (predominantly males) and older adults. In around 30% of patients, not only
ABMAs but also P-ANCAs, usually directed against MPO, are present. The mainstay of
therapy consists of GCs and cyclophosphamide. Furthermore, plasmapheresis should be
performed in patients with pulmonary-renal syndrome and in patients with isolated
glomerulonephritis when there is a chance for renal recovery (reviewed in [69]).

Rarely, DAH may occur as a manifestation of Henoch-Schönlein purpura (HSP) and cryoglubulinemic
vasculitis (CV), both of which are small vessel immune complex vasculitides. HSP (incidence
20 people per 100,000 per year) is characterized by immune deposits including IgA.
It usually affects young children, with a male pre-dominance. The classic triad of
HSP is purpura (due to leucocytoclastic vasculitis of small skin vessels), arthritis
and abdominal pain (due to gastrointenstinal vasculitis). Deposition of immune complexes
to the alveolar basement membrane may lead to immune complex pneumonitis and leucocytoclastic
capillaritis with subsequent DAH. Corticosteroids reduce duration and severity of
joint and abdominal pain but do not prevent the development of nephritis. A wide range
of immunosuppressants has been used to control disease activity, such as azathioprine,
mycophenolate, cyclosporine and cyclophosphamide, yet there is currently not enough
data available from controlled trials to indicate that any of these treatments are
of definite benefit. Regarding cyclophosphamide, a recent study has shown that the
combination of cyclophosphamide and GCs is not superior to GC treatment alone. Controlled
trials are needed to guide treatment strategies in HSP (reviewed in [70]).

Around 2% of patients with CV present with DAH. CV may occur as primary 'essential'
vasculitis or - and much more frequently - as secondary vasculitis, mostly due to
infection with the hepatitis C virus. Typical CV manifestations are purpura, arthritis,
polyneuropathy and glomerulonephritis (membranoproliferative glomerulonephritis type
1) [71]. In essential CV, GC treatment in conjunction with medium- to highly potent immunosuppression
is recommended [11]. For hepatitis C virusassociated CV, anti-viral therapy is indicated. Rituximab may
also be of benefit in the treatment of CV [11].

Small vessel vasculitis with lung involvement and consecutive alveolar hemorrhage
may also develop rarely in collagen vascular diseases (such as systemic lupus erythematosus
and systemic sclerosis).

Panrarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly
affects medium-size arteries and may lead to stenosis or formation of micro-aneurysms,
which can rupture and cause major bleeding. PAN is primary in the majority of patients
but may also occur in association with viral infections, especially with hepatitis
B virus. Apart from constitutional symptoms, peripheral neuropathy, skin involvement
(livedo, purpura, digital ischemia), gastrointestinal involvement with bleeding and
perforation, renal artery stenosis and hypertension are common [72]. Pulmonary involvement (lung infiltrates, pleural effusions) is rare (in around 4%
of patients [72]). For hepatitis B-related PAN, the use of GCs and anti-viral agents is recommended.
Plasma-exchange also seems successful in remission induction [73]. Non-infectious PAN is treated by GCs in conjunction with medium- to highly potent
immunosuppressants.

Large vessel involvement of the lungs is found in two conditions, Takayasu arteritis
and Behcet's disease (BD). Takayasu arteritis is a large vessel vasculitis mainly
affecting young females in Japan and Southeast Asia. Most frequently, subclavian and
carotid arteries are involved followed by adominal aorta and mesentery arteries. Brachiocephalic
involvement may also occur, usually in conjunction with Takayasu arteritis inflammation
at other sites. Isolated pulmonary artery involvement is rare [74]. Stenosis and occlusion is the typical complication, but dilatation and aneurysms
may also be found. Patients should receive GCs and an adjunctive immunosuppressive
agent, such as azathioprine, MTX or cyclophosphamide, for remission induction [73]. Recon-structive surgery should be performed when the patient is in remission if
possible [73]. BD is a rare multisystemic and chronic inflammatory disorder that is associated
with recurrent oral and genital ulcers, eye involvement (uveitis) and skin lesions
(for example, erythema nodosum). It is most commonly found in young males and occurs
most frequently in countries along the old silk route. There is a strong association
with HLA-B51 in BD patients. The most common vascular involvement of BD is venous
thrombophlebitis. Pulmonary artery vasculitis is present in 5% of cases and may lead
to arterial and venous occlusion/thrombosis, aneurysms, infarction, hemorrhage and
arteriovenous shunts. BD is the most common cause of pulmonary artery aneurysms (reviewed
in [75]). If untreated, the mortality rate of BD patients with pulmonary artery aneurysms
is 30% within 2 years. Treatment for BD consists of GCs plus adjunctive conventional
immunosuppressants depending on disease manifestation and activity [76]. GCs plus cyclophosphamide may be effective in the treatment of aneurysmal dilatation.

Importantly, thromboembolisms may occur not only in BD but also in other vasculitides,
especially in AAV [77]. A recent study showed that around 12% of AAV patients develop thromboembolism, usually
during active disease [77].

Vasculitis related to drugs and occupational exposure

Drugs such as propylthiouracil, gemcitabine, trans-retinoic acid and cocaine may also
cause pulmonary capillaritis and DAH and are often associated with the presence of
ANCAs [78]. Moreover, certain occupational exposures, such as to silica from specific farming
tasks related to harvesting, have been suggested to be associated with AAV in case-control
studies [79], but the data are controversial [80].

Pulmonary infections as a comorbidity in vasculitides

Risk of infection under immunosuppressive therapy

Infections in AAVs may be related to immunosuppressive therapy or the severity of
the disease or both [81] and have been reported to occur in 6 to 55% of AAV patients [82,83]. In particular, high doses of GCs (often defined as 30 mg prednisolone/day) and cyclophosphamide
have been shown to be associated with infections in AAVs [84]. The dose of oral cyclophosphamide at the time point of infection as well as the
cumulative oral cyclophosphamide dose were identified as risk factors [84]. Moreover, the rate of infections within the first 3 years of follow-up was related
to the cumulative doses of cyclophosphamide and GCs [84]. Biologics are increasingly used for remission induction in AAV, with similar risk
of infection compared to conventional therapy: in a randomized controlled trial of
oral cyclophosphamide versus rituximab, the rates of infections in both arms were
similar (around 7% of subjects had infections of grade 3 or higher) [44].

In refractory AAV, even more intensive therapy may be administered, as biologics are
often used in conjunction with medium- or highly potent immunosuppression. Serious
infections were reported in 20% of refractory AAV patients treated with rituximab
plus additional medium- or highly potent conventional immunosuppression, most of whom
had pneumonias (14%) [85]. Under anti-thymocyte globulin or deoxyspergualin in combination with GCs, even 40%
and 78% of patients, respectively, suffered from infections [86,87].

Time point and kind of infection during the course of disease

A study on risk factors for major infection in WG found that half of the major infections
occurred within 3 years after WG diagnosis [84]. Furthermore, infections and not active vasculitis represent the main cause of 'early
mortality' (mortality within the first year of diagnosis) in AAVs. 'Early mortality'
was higher in study populations with more severe disease (in the generalized or severe
stage of the disease) who received more intensive immunosuppression (cyclophosphamide
or cyclophosphamide plus plasma exchange) [60]. In summary, patients seem to be most vulnerable to infections shortly after diagnosis.
Whether this relates to the intensive immunosuppression required for remission induction
or whether the disease and disease activity itself also accounts for a suppression
of the immune system and an increased risk of death has not been determined.

Most of the controlled trials in AAV give the rate of infection, but do not specify
the kind of infection [42,43]. Yet, a large retrospective study on WG patients and major risk factors for infections
reported that pneumonia is one of the most frequent infectious complications under
immunosuppression in AAVs [84]. Pneumonia accounted for 36% of all major infections, followed by viral infections
(17%). Likewise, lower respiratory tract infection has been reported as the most frequent
infection in refractory AAV patients treated with rituximab and deoxyspergualin [86,87]. An intensified diagnostic approach including bronchoscopy with bronchoalveolar lavage
is recommended in immunosuppressed patients with pneumonia because of the broad spectrum
of pathogens and the uncertainties of empirical antimicrobial coverage in this population.

Pneumocystis jirovecii pneumonia (PJP) is a dreaded complication of immunosuppression and has been shown
to occur most frequently in patients undergoing intense remission induction therapy
[88]. Furthermore, among AAV patients, those with WG seem particularly at risk of developing
PJP [81]. Without the use of PJP prophylaxis, the incidence of PJP was reported to be up to
20% [82]. Age, as well as a low lymphocyte count before and during therapy and prolonged GC
doses of >15 to 20 mg/day, are risk factors for PJP [88-91]. Although there are no controlled data on PJP prophylaxis in AAV, it is recommended
as infection rates were much higher in trials not using prophylaxis compared to trials
encouraging it [82,92]. Mahr and colleagues [93] reported no more occurrence of PJP since the introduction of PJP prophylaxis. PJP
prophylaxis with trimethoprim/sulfomethoxazole is encouraged by European guidelines
in all patients receiving cyclophosphamide [11].

Conclusion

The AAVs share the features of small vessel vasculitis and a (variable) association
with ANCAs. Pulmonary capillaritis is the classic manifestation of small vessel vasculitis,
occurring in all of the three AAVs. In WG the spectrum of the disease also encompasses
mass formation ('granulomatous disease'), which is most prevalent in the upper and
lower respiratory tracts (that is, pulmonary granuloma). In CSS, 'granuloma formation'
may also be found, though less pronounced; furthermore, asthma and eosinophilic organ
infiltration, such as eosinophilic alveolitis, are hallmarks of CSS. GCs and cyclophosphamide
are the mainstay of remission induction in generalized disease (such as pulmonary
capillaritis), and there is good evidence for the use of maintenance therapy (MTX,
azathioprine or leflunomide) in conjunction with GCs in WG and MPA. Rarely, other
vasculitides are associated with pulmonary manifestations: DAH may also occur in GPS,
HSP, CV and collagen vascular diseases. Pulmonary artery occlusion due to thrombosis
and pulmonary artery aneurysms are a feared complication in BD. Infections, particularly
those affecting the lower respiratory tract, remain a major problem under intense
immunosuppression, including biologics. Yet, it is suggested that PJP prophylaxis
is effective in patients receiving cyclophosphamide.

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